Alzheimer Disease: Scientific Breakthroughs and Translational Challenges.
Alzheimer Disease: Scientific Breakthroughs and Translational Challenges.
复制标题
DOI：
10.1016/j.mayocp.2017.02.011
复制
发表时间：
2017-06
影响因子：
8.9
通讯作者：
Graff-Radford NR
中科院分区：
文献类型：
--
作者：
Caselli RJ;Beach TG;Knopman DS;Graff-Radford NR
阿尔茨海默氏病 (AD) 最初被认为是一种导致早老性痴呆的罕见疾病，但后来被认为是全球任何年龄段痴呆症最常见的原因。它具有延长的临床前阶段，其特征是影像学和脑脊液生物标志物的连续变化，并且在症状性记忆丧失出现十多年前就开始出现微妙的记忆衰退，预示着轻度认知障碍阶段的开始。载脂蛋白 Eε4 等位基因是 AD 的一个普遍且有效的危险因素，促进了对其临床前阶段的研究。大脑 Aβ 淀粉样蛋白水平从临床前到早期痴呆阶段不断增加，随后出现过度磷酸化 tau 相关病理，后者导致认知缺陷和痴呆严重程度。结构和分子成像现在可以概括 AD 生前的神经病理学。早发性家族性AD的常染色体显性遗传形式引发了AD的淀粉样蛋白假说，该假说反过来又引发了旨在清除脑淀粉样蛋白的免疫疗法的治疗试验，但迄今为止的结果令人失望。全基因组关联研究已经确定了多种额外的危险因素，但迄今为止还没有产生有效的替代治疗靶点。当前和未来针对患有脑淀粉样蛋白或具有高遗传风险的症状前个体的试验提供了希望，即在针对已确诊痴呆症患者的试验失败的情况下，早期干预可能会取得成功。迫在眉睫的主要挑战将是昂贵且不完全有效的疾病修饰疗法：谁、何时接受治疗，以及如何支付费用。
Alzheimer’s disease (AD) was originally conceived as a rare disease that caused presenile dementia but has come to be understood as the most prevalent cause of dementia at any age worldwide. It has an extended preclinical phase characterized by sequential changes in imaging and cerebrospinal fluid biomarkers with subtle memory decline beginning more than a decade before the emergence of symptomatic memory loss heralding the beginning of the mild cognitive impairment stage. The apolipoprotein Eε4 allele is a prevalent and potent risk factor for AD that has facilitated research into its preclinical phase. Cerebral Aβ amyloid levels build from preclinical through early dementia stages followed by hyperphosphorylated tau-related pathology, the latter driving cognitive deficits and dementia severity. Structural and molecular imaging can now recapitulate the neuropathology of AD antemortem. Autosomal dominant forms of early onset familial AD gave rise to the amyloid hypothesis of AD that in turn has led to therapeutic trials of immunotherapy designed to clear cerebral amyloid but to date results have been disappointing. Genome wide association studies have identified multiple additional risk factors but to date none have yielded an effective alternate therapeutic target. Current and future trials aimed at presymptomatic individuals either harboring cerebral amyloid or at genetically high risk offer the hope that earlier intervention might yet succeed where trials in patients with established dementia have failed. A major looming challenge will be that of expensive, incompletely effective disease modifying therapy: who and when to treat, and how to pay for it.
登录
查看更多内容
影响因子：
64.8
作者：
De Strooper, B;Saftig, P;Van Leuven, F
通讯作者：
Van Leuven, F
DOI：
10.1016/j.jalz.2013.01.004
发表时间：
2014-01
期刊：
Alzheimer's & dementia : the journal of the Alzheimer's Association
影响因子：
--
作者：
Caselli RJ;Locke DE;Dueck AC;Knopman DS;Woodruff BK;Hoffman-Snyder C;Rademakers R;Fleisher AS;Reiman EM
通讯作者：
Reiman EM
影响因子：
9.9
作者：
Boeve, BF;Maraganore, DM;Petersen, RC
通讯作者：
Petersen, RC
影响因子：
8.9
作者：
Caselli, Richard J.;Langbaum, Jessica;Robert, Jason S.
通讯作者：
Robert, Jason S.
影响因子：
29
作者：
Dean, Douglas C., III;Jerskey, Beth A.;Chen, Kewei;Protas, Hillary;Thiyyagura, Pradeep;Roontiva, Auttawat;O'Muircheartaigh, Jonathan;Dirks, Holly;Waskiewicz, Nicole;Lehman, Katie;Siniard, Ashley L.;Turk, Mari N.;Hua, Xue;Madsen, Sarah K.;Thompson, Paul M.;Fleisher, Adam S.;Huentelman, Matthew J.;Deoni, Sean C. L.;Reiman, Eric M.
通讯作者：
Reiman, Eric M.